The overall goal of this Program is to examine a protective role for innate immunity in autoimmune disease. Two murine models of autoimmunity will be characterized, i.e. systemic lupus erythematosus and rheumatoid arthritis. Four highly interrelated projects are proposed involving five senior investigators. The underlying theme connecting the four projects is the intimate role innate immunity plays in antigen clearance. Three of the projects will examine how self-reactive B- lymphocytes are negatively regulated by antigen in two well- characterized immunoglobulin transgenic models, i.e. hen lysozyme and dsDNA. Clonal deletion and receptor editing of self-reactive B- lymphocytes will be examined in mice deficient in innate proteins DNAse I, IgM, MBL, C1q, C4 and receptors CD21/CD35. Moreover, novel transgenic mice bearing an auto-reactive transgenic receptor or deficiency in Fas will be constructed using a conditional knock-in approach. The fourth project will examine if innate immunity is involved in T cell tolerance and/or elimination of self-antigen in the rheumatoid arthritis T-cell transgenic model. The significance of the program is that it not only addresses fundamental questions on regulation of adaptive immunity but could lead to novel therapies. Dissection of common pathways of innate immunity that protect against autoimmune disease could lead to therapeutic approaches with broad applications. A major strength of the Program is that it brings together senior investigators, each with specialized expertise, to interact in a synergistic manner.